Autoimmune diseases are prevalent in women during child-bearing years, yet pregnant women are excluded from experimental treatments for autoimmune diseases because of unknown effects on the fetus and because of changes that occur in the immune system during pregnancy. These changes make it difficult to predict how the maternal immune system would respond to tolerance-inducing strategies. This project has been created to address questions concerning how the maternal immune system changes during pregnancy to accept the "foreign" fetus. It is unclear whether the maternal immune system is tolerant to or simply ignores fetal antigens. Female mice will be mated with either syngeneic or allogeneic males then, lymphoid tissues will be evaluated for changes in the T cell receptor repertoire, activation antigens, and memory/naive phenotype of T cells that would indicate exposure to fetal antigens. These tissues will also be assessed for changes in lymphokine secretion, and expression of costimulatory molecules, either of which could modulate the type of immune response initiated towards these antigens. Inability to see such changes could occur for several reasons, including extremely low precursor frequencies of antigen specific cells. To examine the latter possibility, experiments will also be performed with female transgenic mice in which the majority of T cells express a transgenic T cell receptor specific for a known antigen mated to male mice expressing that antigen. The use of TCR transgenic mice will allow study of the fate of a large clonal population of maternal T cells in the presence of paternal antigens. Additional studies will address how changes in the maternal immune system effect tolerance induction in mouse models of autoimmune disease and what effect maternal tolerance induction during pregnancy will have on the fetus. 1. Vacchio MS, Papadopoulos V, Ashwell JD. Steroid production in the thymus: implications for thymocyte selection. J Exp Med 1994;179:1835-46. 2. Vacchio MS, Yang Y, Ashwell JD. Nuclear receptors and thymocyte apoptosis: shaping the immune repertoire. Apoptosis 1994;:179-194. 3. King LB, Vacchio MS, Ashwell JD. To be or not to be: mutually antagonistic death signals regulate thymocyte apoptosis. Int Arch Allergy Immunol 1994;105:355-8. 4. King LB, Vacchio MS, Hunziker R, Margulies DH and Ashwell JD. A targeted glucocorticoid receptor antisense transgene increases thymocyte apoptosis and alters thymocyte development. Immunity 1995 (in press)